Lung and airway diseases are significant health burdens with few effective therapies. Regenerative medicine approaches, such as the stimulation of endogenous repair mechanisms or replacing diseased cells with healthy cells, have great potential. In addition to their roles in innate immunity accumulating data suggest that tissue resident alveolar macrophages can promote either lung regeneration or remodeling, depending on their polarization and microenvironmental cues. As such, immune-epithelial interactions provide an attractive target to promote alveolar regeneration and stop or reverse alveolar damage. In contrast to the alveoli, nearly nothing is known about the identities and roles of leukocytes during airway repair/remodeling. Moreover, most data regarding alveolar and airway injury/repair, including potential modulation by immune cells, are derived from mouse models and there is a dearth of in vivo data regarding endogenous repair in large animal models. This is significant because the lungs of rodents have striking anatomical and cellular differences from human lungs. This proposal addresses these knowledge gaps by testing the hypothesis that myeloid cells and type 2 inflammation are critical modulators of epithelial stem cell behaviors during homeostasis and in response to airway and alveolar injury in mice and nonhuman primates. This hypothesis is based on published data regarding macrophages in alveolar regeneration and unpublished data regarding airway-associated macrophages. Specific Aim 1 will establish the molecular identities and ontogenies of two previously undescribed airway- associated myeloid populations: Intraepithelial airway macrophages (IAMs) and mesenchyme-associated airway myeloid cells (MAMCs). Single cell RNA sequencing, immunofluorescence and flow cytometry will be used to determine how these populations change over the course of injury/repair. In vivo and in vitro experiments will determine how these cells affect the quiescence, proliferation and differentiation of airway basal cells ? stem cells that maintain the pseudostratified airway epithelium. Finally, bronchial thermoplasty will be developed as a nonhuman primate platform to study regeneration of the airway epithelium, including immune-epithelial interactions. Building upon previous data, Specific Aim 2 will use genetic mouse models to test the hypothesis that Il33 activates group 2 innate lymphoid cells (ILC2S) to secrete Il13 during regeneration of the alveolar epithelium after pneumonectomy (PNX). Genetic mouse models will be used to test the related hypothesis that Il13, in turn, polarizes recruited inflammatory monocytes toward an M2-like phenotype that promotes repair. Lastly, two nonhuman primate models of alveolar injury will be developed to test the hypothesis that the inflammatory milieu, including myeloid cells and type 2 cytokines, modulate the histologic outcome of alveolar injury. Together, these data will establish immune-epithelial interactions as a therapeutic target to prevent or reverse the debilitating effects of pathologic lung remodeling.